Besides fulfilling their typical reproductive functions, sex hormones markedly affect the cerebral function. Depending on the cerebral region, type of cells as well as age and gender of an individual, the same sex hormones may inhibit or stimulate the brain [1]. At the cellular and sub-cellular level, the difference between male and female sex hormones blurs. The same androgens, estrogens and gestagens exert their effects in women and men. The direction and strength of their action are determined by the predominance of one group of hormones over the remaining ones. The experimental animal studies, assessing the relation between sequels of severe brain diseases and gender, demonstrate protective effects of female sex hormones on the cerebral structure. Unfortunately, results and conclusions of experimental studies, mostly performed in rats and mice, do not translate into similar conclusions of human studies.

The brain requires protection of tissues against effects of harmful causative factors: trauma, ischaemia, β-amyloid accumulation, induced by ischaemia of free oxygen radicals and toxic excitatory amino acids [2]. Protective effects of estrogens were described in numerous animal studies and models of cell lines, yet the precise mechanism of this activity has not been fully explained [3]. Estrogens exert their key genomic effects due to direct action on an intercellular estrogen receptor type α (ERα) or β (ERβ). ERα plays a pivotal role in regulation of reproductive neuroendocrine functions. ERβ is involved in regulation of non-reproductive functions [4]. The estrogen-receptor complex triggers the genomic mechanism and initiates the synthesis of neuropeptides, neurotransmitters, nitric oxide, etc. [5, 6]. The activation of this genomic mechanism may take even several hours [7].

An alternative, extra-genomic pathway of estrogen action involves activation of the system of intracellular signalling substances and phosphorylation of numerous membranous and cytoplasmic proteins [5, 8, 9]. In the non-genomic mechanism, the estradiol molecule binds directly to the membrane receptor site and acts almost immediately, within several minutes, at most. Estrogens reduce the threshold needed to induce seizures [7].

Estrogens reduce the number of active GABAA receptors and GABAergic synapses as well as the capacity of receptor binding to agonists; on the other hand, they enhance the NMDA-dependent inductive reaction of the Purkinje cells to the action of stimulating amino acids [7,10]. 17β-estradiol increases the number of active NMDA receptors in the hippocampal CA1 region, modulates their function and regulates the process of synaptogenesis [2, 11]. Additionally, chronic administration of estrogens results in increased density of dendritic processes of pyramidal cells [1]. Estrogens increase the cerebral concentration and activity of progesterone, muscarine, dopaminergic and serotoninergic type 2 receptors and decrease the number of active β-adrenergic and serotoninergic type 1 receptors [11, 12]. Moreover, estrogens markedly increase the activity of choline acetyltransferase and extent of degradation of monoamine oxidase (MAO), which improves the availability and transport of serotonin within the CNS. Even the physiol
ogical concentrations of 17β-estradiol play an important role in regulation of cerebral glucose metabolism. The administration of estrogens to ovariectomised animals increases the glucose metabolism by 20-30% [13].

Neuroprotective action of estrogens is complex and involves two mechanisms: indirect (affecting cerebral vascularisation) or direct (independent of blood flow) [14, 15]. The indirect mechanism is associated with improved function of the vascular endothelium and increased blood flow through the brain [14, 16, 17]. Increased blood flow, due to widening of the vascular lumen, increases the surface of exchange between blood and cerebral tissues and, according to the Renkin-Crone model, facilitates transport through the cerebral barriers. The flow-dependent mechanisms of neuroprotection, which estrogens are responsible for, also include platelet aggregation inhibition, intravascular adhesion of leukocytes, thromboxane-induced thrombotic and vasoconstrictive effects [14, 17]. By increasing the cerebral blood flow, estrogens improve the availability of oxygen and glucose to nerve cells, thus improving their functions [1]. In animal studies, the efficacy of indirect mechanism was confirmed both for low and high doses
of estradiol [14].

The direct neuroprotective mechanism of estrogens regards the CNS neurones and glial cells [17]. Protective effects of estrogens are multidirectional and may depend on potent antioxidant properties, regulation of metabolism and homeostasis of calcium ions, increased uptake and use of glucose by cerebral tissues, blockade of toxic activating amino acids, induction of antiapoptotic proteins, neurotrophins and apolipoprotein, modification of the cellular and humoral immune response and inhibition of immediate-response genes.

Given such multi-directional neuroprotective effects of estrogens, it is difficult to determine how important the individual elements are. The non-genomic mechanism is used to promote the antioxidant activity, prevent the intracellular accumulation of calcium ions, and enhance the activation of cyclic adenosine monophosphate (c-AMP) and mitogen-activated protein kinase (MAPK) [18, 19]. 17β-estradiol, by modulating the activity of neutrophins, affects the process of neurogenesis and neuronal differentiation, induces the growth of neurons, lengthens their survival, and stimulates regeneration of nervous processes of various CNS cells [15, 20]. It also acts by inducing the brain-derived neurotrophic factor (BDNF), glial cell-derived neutrophic factor (GDNF), basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) [15, 21].

Estrogens exert substantial effects on immune cells. Depending on the estradiol dose, these effects may be pro- or anti-inflammatory. High doses of estradiol, thus elevated concentration of estrogens in blood serum, have pro-inflammatory action by activating microglial cells. The administration of a small estradiol dose, resulting in low hormone concentration in blood serum, inhibits the microglial activation, leading to anti-inflammatory response [19]. Likewise, extreme concentrations of estradiol either decrease or increase the activity of macrophages and production of cytokines and T lymphocytes [3, 19]. The modification of inflammatory response after administration of estrogens depends on direct effects on ERα, yet not ERβ [22].

Estrogens may activate the genes responsible for processes protecting the cells against apoptosis [23]. 17β-estradiol regulates the Bcl-2 anti-apoptotic proteins (Bcl-2, Bfl-1) [8, 15, 24, 25]. Moreover, induction of immediate early genes (IEG) is essential for programmed cell death [26]. Besides the promotion of Bcl-2 synthesis, the ability of estrogens to inhibit the expression of these genes is a significant element of neuroprotection.

Some of the protective properties of estrogens are likely to depend on the presence of brain cerebral apolipoprotein (ApoE) [27]. There is a direct correlation between the brain concentration of ApoE and levels of estrogens. The concentration of ApoE varies depending on the ovulation cycle phases and increases after the administration of 17β-estradiol. ApoE, like Bcl-2, may act as a potent antioxidant and prevent the cell death under the oxidative stress conditions [21, 28]. When the nervous structures are damaged due to any causative factor, ApoE plays a relevant role in metabolism and redistribution of free molecules of cholesterol and phospholipids. The supply of estrogens may affect the ApoE-dependent regenerative and repairing processes in the brain [21].

As potent vasodilators, estrogens prevent unfavourable changes in cerebral perfusion. Their administration increases the total and regional cerebral blood flow by about 30%. When the brain is exposed to any destructive factor, their role is to maintain the cerebral perfusion at a proper level. Estrogens either affect the muscarine receptors, increasing their number and activity of choline acethyltranspherase, or produce nitric oxide (NO). The synthesis of nitric oxide is regulated by sex hormones. Even the physiological level of estradiol increases the activity of transmembrane and neuronal NO synthesis. The supply of exogenous estradiol additionally increases the synthesis of NO, particularly in the cerebral endothelium [24, 29].

Biological action of NO is not limited by any barriers; as a simple, lipophilic inorganic gas, nitric oxide may easily diffuse from its site of production to target cells. Dilatation of cerebral capillaries caused by estrogens may result from increased synthesis and release of nitric oxide, inhibition of its degradation or imbalance of vasoactive prostaglandins. The estrogen-related increase in synthesis and release of endothelium-derived nitric oxide is totally blocked by tamoxifen, an anti-estrogen drug, which indicates that vasodilatation depends directly on the hormone-estrogen receptor interactions [30].

Cholinergic stimulation and increased release of nitric oxide are beneficial for prevention of cardiovascular diseases, particularly evident in pre-menopause women. The role of estrogens in regulation of cerebral vascular flow is evidenced by the fact of age-related progression of dysfunction of endothelial cells and decreased production of nitric oxide in animals after bilateral ovariectomy with increased risk of myocardial ischaemic disease and ischaemic changes in the brain [31]. Due to uncontrolled stimulation of nitric oxide synthetase and excessive release of acetylcholine from the muscarinic cholinergic fibre endings, estrogen hormonal substitution may lead to rapid increase in blood flow, increased permeability through the cerebral barriers and brain oedema [32].

Under physiological conditions, neuroprotective mechanisms of estrogens depend on age, gender, hormonal status, which is shown by different incidence rates of brain stroke in various age groups of men and women. At the age of 45-54, the incidence of diagnosed strokes in women is by half lower than in men. This difference blurs in the age group of 65-74 years. According to numerous animal studies, the stroke size, caused by a comparable mechanism, is always bigger in males (irrespective of age) and in older females than those at the reproductive age [12, 17]. A significantly higher mortality amongst males compared to females in the group of young animals, caused by experimental brain stroke, becomes insignificant in the group of older animals [18]. Likewise, experimental stroke-related cerebral destructive changes, their extent and type are definitely smaller in young animals with intact ovaries than in females after surgical or pharmacological sterilization, compared to males. The comparison of histopathologi
cal findings in males and ovariectomised females shows comparable changes [33]. 

Exogenous estrogens markedly affect the vascular endothelium. Their administration increases the exo- and endocytic activity of the cerebral endothelium. It is highly likely, that due to endocytic uptake of extracellular elements, estrogens are responsible for increased permeability of the cerebral barrier system. Both the deficiency and excess of estrogens are harmful for cerebral barrier stability. Ageing-related decreased concentrations of endogenous estrogens and dysfunction of estrogen receptors impair the barrier mechanisms, including the discontinuity of the cerebral barrier system. The permeability of the cerebral barrier system is significantly higher in hypoestrogenic individuals compared to sexually mature animals [34]. If in young animals with hypoestrogenism induced by surgical or pharmacological sterilization the concentration of estrogens is supplemented, the permeability through the cerebral barriers decreases. Paradoxically, the administration of estrogens to old animals will result in more p
ronounced barrier dysfunction [34]. Unfavourable effects of chronic administration of estrogens to post-menopause women on the function of blood-CSF barrier were confirmed in earlier experimental studies. The estrogen replacement therapy increased the permeability to multi-molecular compounds [35].

Gestagens belong to the second group of sex hormones of potent neuroprotective action. The best-known representative of this group is progesterone, yet the actual protective effects on brain tissues are exerted by its derivatives: 5α-dihydroprogesterone (DHP) and 3α5α-tetrahydroprogesterone (THP, allopregnanolon). Progesterone and its natural metabolites modulate the brain function directly through the classical intracellular progesterone receptor (hPR) and membrane progesterone receptor (25-Dx) or indirectly by increasing the GABAA activity or inhibiting the excitatory amino acids and nicotinic receptor activity [10, 36, 37, 38].

The biological effects of progesterone and its derivatives on the progesterone receptor involve stimulation or inhibition of DNA transcription and protein synthesis. The psychotropic effect observed after progesterone, which is dependent on activation of GABAA receptors, results from bioconversion of progesterone to 5α-dihydroprogesterone and allopregnanolon [36, 39]. The activation of post-synaptic GABAA receptors leads to inhibition of post-synaptic neurones. Allopregnanolon increases the sensitivity of cortical synaptoneurosomes to γ-aminobutyric acid, opens the chlorine channels and promotes the transport of chlorine ions [40, 41]. The activation of GABAA receptors potentiates the inhibition processes in the Purkinje cells in the cerebellum and mediates the gonadotropin release in the hypothalamus. The neuroprotective action of THP depends on the function of the type A GABA receptor [40]. THP is a potent modulator of the GABAA receptor. The impact through the GABAA receptor is responsible for anticonvulsa
nt action and inhibition of brain function. THP has strong anxiety-relieving properties. In patients with diagnosed  depression, the concentration of THP in CSF is markedly lower.

One of neuroprotective mechanisms, THP is responsible for, is prevention of neuronal death. Blocking the calcium channels, THP decreases amino acid-induced irreversible changes in the concentration of intracellular calcium ions, which was observed in neurones of the hippocampal CA1 region [42]. Irrespective of progesterone influence on GABA receptors, THP limits the effects of amino acids activating NMDA and AMPA receptors, thus prevents the toxicity of glutaminates. After binding to the 25-Dx receptor, progesterone and its derivatives modify the properties of the cell membrane and inhibit the reaction of neurone excitation [39]. THP protects against damage to the hippocampal CA1-CA3 pyramidal cells after exposure to a causative factor, e.g. hypoxia. Increased concentrations of progesterone derivatives decrease the amplitude of potentials induced in the pyramidal layer of the hippocampal CA1 region [10].

Another possible mechanism of progesterone neuroprotection is inhibition of free oxygen radical-stimulated peroxidation of lipid membranes and selective regulation of gene expression. Anti-oxidative properties of gestagens are essential for neuroprotection [37]. The protective action of progesterone and its derivatives is regulated by the glial cells [18]. The trophic effects of gestagens include promotion of nerve cell growth, increase in the number of new dendritic processes, formation of new synapses, stimulation of myelinisation and re-myelinisation of CNS [36, 43, 44, 45]. After progesterone administration, the Schwann cells increase the production of myelin, which results in increased thickness of the myelin sheath, e.g. during re-myelinisation of damaged axons [46, 47]. Reduced concentrations of progesterone and its derivatives have a substantial neuromodulatory effect on brain function [48]. In cases of long-term progesterone therapy, its sudden withdrawal will lead to symptoms of severe brain damage
and seizures, which belong to the withdrawal syndrome [49]. A sudden discontinuation of antiepileptic treatment leads to a similar clinical course. A sudden decrease in seizure threshold is the cause of life-threatening status epilepticus.

Testosterone and other androgen derivatives do not have neuroprotective effects. In males, who have particularly high testosterone levels, it promotes immunosuppression. This translates to increased risk of pro-inflammatory effects, which increase trauma-related CNS neurodegenerative changes [50]. The adverse effects of testosterone are indirectly evidenced by the fact that neuroprotective properties of estrogens in males depend on inhibition of production and release of testosterone [14].

The role of estrogens and gestagens in maintaining homeostasis and balance within the cerebral structures is similar and equally important. However, if the brain interior is impaired by a potent damaging factor, the protective effects of gestagen derivatives appear to be markedly stronger. The maintenance of sex hormone balance is essential for prevention of sequels of severe cerebral diseases. There are certain regulatory preventive measures between various hormones and groups of sex hormones, which are to maintain the relative hormonal balance.

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address:

*Cezary Pakulski
Centrum Leczenia Urazów Wielonarządowych
SPSK nr 1 w Szczecinie
ul. Unii Lubelskiej 1
71-252 Szczecin
tel./fax: 91 425 3581
e-mail: cluw@sci.pam.szczecin.pl

received: 08.10.2010
accepted: 04.02.2011